The present invention, in some embodiments thereof, relates to therapy and, more particularly, but not exclusively, to novel methodologies for treating medical conditions such as proliferative diseases and disorders, and drug resistant as well as multidrug resistant (MDR) conditions in particular.
Cancer is a major cause of mortality worldwide. Despite advancements in diagnosis and treatment, there remains a great need for novel methods of treating cancer and for identifying novel agents and approaches for overcoming proliferation of cancer cells, particularly drug resistant cancer cells.
Multidrug resistance (MDR) towards chemotherapeutic agents poses a major impediment towards curative chemotherapy of various human malignancies. In this respect, MDR is an extensively studied mechanism of anticancer drug resistance. MDR is mediated by members of the ATP-binding cassette superfamily of transporters including ABCB1 (P-glycoprotein), ABCC1 (MRP1) and ABCG2 (BCRP). Recognizing a plethora of hydrophobic, hydrophilic and amphiphilic cytotoxic substrates, these ATP-driven efflux pumps extrude structurally distinct endobiotics and xenobiotics out of malignant tumors, many of which are key antitumor agents, thereby resulting in a wide spectrum of drug resistance.
Imidazoacridinones (IAs) are a class of planar imidazoacridinone-based cytotoxic fluorochromes which exhibited significant clinical activity against colorectal and breast cancer [Skladanowski et al. Mol Pharmacol 1996, 49:772-780]. IAs are weak bases which are hydrophobic in a non-protonated state, but more water-soluble in a protonated, positively charged state. The structure of the exemplary IAs C-1330, C-1375, C-1379 and C-1311 is shown in FIG. 1, and includes an imidazole ring, as well as an amine group (depicted as “NRa,b” in FIG. 1), both of which comprise a weakly basic nitrogen atom which may become protonated, and therefore positively charged, under physiological conditions in acidic organelles such as lysosomes and endosomes.
IAs are somewhat similar in structure to acridine orange, an established fluorophore that is known to concentrate within lysosomes in viable cells. Acridine orange also binds to DNA, a phenomenon which is utilized for staining DNA. Other acridine-based compounds, including IAs, have also been shown to bind to DNA [Dziegielewski et al., Biochem Pharmacol 2002, 63:1653-1662; Bram et al., Mol Pharmacol 2009, 75:1149-1159]. However, DNA binding by IAs does not appear to contribute significantly to the cytotoxic activity of IAs [Dziegielewski et al., Biochem Pharmacol 2002, 63:1653-1662]. Instead, the cytotoxic activity of IAs appears to be primarily a result of topoisomerase II inhibition [Skladanowski et al. Mol Pharmacol 1996, 49:772-780]. U.S. Patent Application No. 20100137351 and Bram et al. [Mol Pharmacol 2009, 75:1149-1159] describe IA compounds characterized by anti-cancer activity, some of which are extruded out of MDR cells via the MDR efflux pump ABCG2. In general, IA compounds lacking a hydroxyl group at one of the R1-R3 positions shown in FIG. 1 and/or with a longer distal aliphatic side chain (NH(CH2)nNRa,b in FIG. 1) were not recognized as transport substrates by ABCG2 and hence overcame the MDR displayed by ABCG2-ovrexpressing cells.
Sunitinib is a member of a family of pyrrole substituted 2-indolinone compounds, reported as being receptor tyrosine kinase inhibitors (see, U.S. Pat. Nos. 6,573,293 and 7,211,600). Sunitinib inhibits cellular signaling via a variety of receptors which play a role in tumor angiogenesis and tumor cell proliferation. Hence, the simultaneous inhibition of these receptors promotes reduced tumor vascularization (i.e. exhibits an anti-angiogenic effect) and cancer cell death. However, the diversity of receptors targeted by sunitinib results in many side effects, such as hand-foot syndrome, stomatitis and other dermatological toxicities.
Photodynamic therapy (PDT) is a medical technique wherein a photosensitizer applied to a subject is excited by illumination from an external light source. The excited photosensitizer may produce reactive oxygen species (ROS) capable of killing cells and/or closing/opening blood vessels. The history, mechanism of action and applications of PDT have been reviewed, for example, by van den Bergh and Ballini [in Lasers in Ophthalmology—Basic, Diagnostic and Surgical Aspects, edited by Fankhauser and Kwasniewska, 2003, Kugler Publications, The Hague] and Sharman et al. [Adv Drug Delivery Rev (2004) 56:53-76].
A photosensitizer is generally selected to be relatively non-toxic in the absence of light, such that directing illumination to a particular site provides a localized phototoxicity. Photosensitizers used for PDT are typically porphyrins and structurally-related compounds such as chlorins, texaphyrins and phthalocyanines, or porphyrin precursors such as aminolevulinic acid. Rhodamine dyes have also been used for PDT [Haghighat et al., Laryngoscope (1992) 102:81-87].
It has been reported that photosensitizers differentially target certain intracellular organelles such as mitochondria, endoplasmic reticulum or lysosomes, and that a photosensitizer which targets lysosomes causes release of proteolytic lysosomal enzyme [Quiogue et al., Proc Soc Photo Opt Instrum Eng (2009) 7380:1-8]. However, mitochondria are more often considered as an effective target for photosensitizers [Quiogue et al., Proc Soc Photo Opt Instrum Eng (2009) 7380:1-8].
The combination of administration of chemotherapeutic agents and PDT with a photosensitizer has been studied. U.S. Patent Application No. 20100256136 describes a method of enhancing PDT efficacy in tissue which expresses ABCG2 by introducing a tyrosine kinase inhibitor prior to PDT. The tyrosine kinase inhibitor is introduced in order to inhibit efflux of the PDT photosensitizer.
Phthalocyanine-based PDT has been used in combination with doxorubicin in order to overcome doxorubicin resistance mediated by accumulation of doxorubicin in cellular organelles. It has been reported that the PDT disrupts endosomal/lysosomal membranes in order to release the doxorubicin from organelles to the nuclei, where doxorubicin exerts a cytotoxic effect [Hsu et al., IFMBE Proceedings (2009) 23:1451-1454].
PDT was reported to potentiate the efficacy of doxorubicin, and vice versa, with the combination being most effective when doxorubicin was administered immediately after light exposure [Kirveliene et al., Cancer Chemother Pharmacol (2006) 57:65-72]. PDT followed by administration of doxorubicin has been suggested as a technique for overcoming MDR in cancer cells [Lou et al., Int J Cancer (2006) 119:2692-2698]. In several studies, it has been reported that the cytotoxicity of doxorubicin, an anthracycline drug which targets topoisomerase II and intercalates into DNA, can be enhanced by laser irradiation [Lanks et al., Cancer Chemother Pharmacol (1994) 35:17-20; Gao et al., Cancer Chemother Pharmacol (1997) 40:138-42]. Some anthracyclines have been proposed as potential photosensitizers for PDT [Koceva-Chyla et al., Cell Biol Int (2006) 30:645-652; Li and Chignell, Photochem Photobiol (1987) 45:565-570].
Additional background art includes Koceva-Chyla et al. [Cell Biol Int (2006) 30:645-652] and Dallbrida et al. [Circulation (2007) 116:II 311] and Gotink et al. Clin Cancer Res. 2011; 17(23):7337-46.